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T*
[(le)25.3(a)15(d)-294.8(to)-284.6(a)15(c)0(u)25.4(t)16.1(e)-301.8(t)16.1(o)16.2(x)0(i)26.5(c)0(i)25.3(t)16.1(ie)25.3(s)-294.6(v)0(i)26.5(a)-296(co)25.4(m)15(p)0(l)26.5(e)15(me)24.2(n)16.2(t)-300.7(a)15(c)15(t)0(i)26.3(v)16.2(at)25.3(io)26.5(n)-294.8([)0(3)26.6(5)16.2(,)13.9(3)0(6)26.6(])0(,)-281(a)0(n)]TJ
0 -1.1174 TD
[(e)15(f)0(f)26.7(e)0(c)24.3(t)-197.1(t)16.1(h)0(a)25.4(t)-197.1(a)15(l)16.1(so)-186.3(a)15(p)16.2(pe)25.4(ar)25.5(e)15(d)-196.9(a)15(f)0(t)26.5(e)0(r)-181.9(t)0(r)26.5(e)0(a)24.3(t)16.1(me)24.2(n)16.2(t)-197.1(of)-180.7(no)26.6(rm)25.4(a)15(l)-197.1(d)16.2(o)0(n)26.6(o)16.2(r)-196.9(s)0(e)25.6(r)0(u)26.6(m)]TJ
0 -1.1116 TD
[(w)15.3(i)0(t)26.3(h)-254.5(C)15.2(p)16.2(G)-249.6(O)0(D)24.9(N)0(-)25.8(P)16.3(T)-255.7([)16.2(3)16.2(3)0(])26.6(.)-251.1(In)-238.3(r)16.2(a)0(t)25.3(s)0(,)-234.7(C)0(p)25.6(G)-249.6(OD)24.9(N)15.3(-)0(P)26.8(T)-250(we)24.6(re)-239.5(s)16.4(t)0(r)26.5(o)0(n)26.6(g)16.2(er)]TJ
T*
[(p)16.2(r)0(o)26.6(m)0(o)25.4(t)16.1(er)25.5(s)-335(o)0(f)-324.7(t)16.1(hr)26.6(o)16.2(m)0(b)25.4(o)16.2(cy)25.4(to)26.5(p)16.2(e)0(n)25.4(i)0(a)25.3(,)-337.5(a)15(n)16.2(em)24.2(i)16.1(a)0(,)-322.5(o)0(r)-324.7(n)16.2(e)15(u)0(t)26.5(r)0(o)26.6(p)16.2(en)25.4(ia)-326(t)16.1(h)16.2(an)]TJ
T*
[(th)26.5(e)-342.1(c)15(or)26.6(re)25.5(s)16.4(p)0(o)26.6(n)0(d)26.6(i)16.1(ng)-330.5(C)15.2(p)0(G)-331.4(O)15.3(DN)24.9(-)16.2(P)0(O)-331.2([)16.2(37)26.6(];)-330.6(a)15(n)16.2(d)-346.7(i)16.1(n)-340.9(m)15(ic)25.3(e)15(,)-343.2(th)26.5(e)-342.1(P)16.3(T-)]TJ
0 -1.1174 TD
[(b)16.2(a)0(c)24.3(k)0(b)26.6(o)16.2(ne)-516(sh)26.8(o)16.2(w)0(e)24.6(d)-531(a)-526.4(s)16.4(yn)26.6(er)25.5(g)16.2(i)0(s)26.7(t)0(i)26.3(c)-526.4(ef)25.5(fe)25.5(c)15(t)-531.1(i)16.1(n)-531(t)16.1(h)16.2(e)-532.2(i)16.1(nd)26.6(u)16.2(c)0(t)25.3(i)0(o)26.5(n)-525.2(of)]TJ
0 -1.1116 TD
[(a)15(r)0(t)26.5(h)0(r)26.6(i)0(t)26.3(i)16.1(s)-340.7([)0(3)26.6(8)16.2(].)-327(Mo)25.7(s)16.4(t)-341(im)25.2(p)16.2(o)0(r)26.6(t)0(a)25.3(n)16.2(tl)26.3(y)16.2(,)-343.2(h)16.2(o)0(w)25.7(e)15(ve)25.4(r,)-327(C)15.2(p)0(G)-325.6(O)0(D)24.9(N)15.3(-P)26.8(T)-342.1(a)15(c-)]TJ
T*
[(c)15(o)0(u)26.6(n)0(t)26.5(e)15(d)-289.1(f)0(o)26.6(r)-289(d)16.2(r)0(a)25.5(m)15(at)25.3(i)16.1(c)-290.2(de)25.4(s)16.4(t)0(r)26.5(u)0(c)25.4(t)16.1(io)26.5(n)-289.1(a)15(nd)-278.7(r)16.2(e)15(du)26.6(ce)24.3(d)-289.1(f)16.2(un)26.6(c)15(t)0(i)26.3(o)0(n)26.6(a)15(li)26.3(ty)-273(of)]TJ
0 -1.1174 TD
[(ly)26.5(m)15(p)0(h)26.6(o)16.2(id)-255.8(o)16.2(r)0(g)26.6(a)15(ns)-255.4(i)16.1(n)-266(m)15(i)0(c)25.3(e)-267.2([3)26.6(9)16.2(])0(.)]TJ
1.0137 -1.1116 TD
[(PT)-204.8(or)-203.8(other)-202.6(modications)-206.9(to)-203.9(protect)-206.1(against)-205.9(exonucleolytic)]TJ
-1.0137 -1.1116 TD
[(degradation)-194.4(can)-195.7(be)-193.4(avoided)-194.5(if)-192.4(DNA)-196(molecules)-193.3(lack)-196.9(open)-189.9(ends)]TJ
0 -1.1174 TD
[(like)-397.5(in)-394(covalently-closed)-399.2(dumbbell-like)-398.5(structures)-393.3([4042].)]TJ
0 -1.1116 TD
[(By)-250.9(this)-252.1(general)-253.2(design)-249.6(principle,)-252.2(we)-251.9(developed)-255.4(a)-249.9(new)-253(family)]TJ
T*
[(of)-313.2(TLR-9)-308.4(agonists)-315.1(by)-307.5(the)-315.6(name)-307.5(of)-313.2(double)-313.2(stem-loop)-311.8(immu-)]TJ
T*
[(nomodulators)-257.6(\(dSLIM)]TJ
/F5 1 Tf
7.3823 0 0 6.5614 150.4629 324.0566 Tm
()Tj
/F4 1 Tf
9.843 0 0 9.843 156.3023 319.6913 Tm
[(\).)-252.2(dSLIM)-255.1(are)-253.3(synthesized)-257.4(by)-255.6(ligation)]TJ
-9.5784 -1.1174 TD
[(of)-589.7(two)-591.8(identical)-589.9(DNA)-593.4(molecules)-590.7(with)-593(stable)-590.7(stem-loop)]TJ
0 -1.1116 TD
[(structures,)-206.6(resulting)-201.3(in)-203.9(covalently)-205(closed)-198.9(molecules)-204.8(of)-203.8(natural)]TJ
T*
[(DNA)-322.7(\(i.e.,)-320.1(with)-322.3(a)-319(3)]TJ
/F5 1 Tf
7.9772 0 TD
()Tj
/F4 1 Tf
.2477 0 TD
.3202 Tc
(,5)Tj
/F5 1 Tf
1.0713 0 TD
0 Tc
()Tj
/F4 1 Tf
.2534 0 TD
[(-phosphorodiester)-320.3(backbone\),)-327.8(which)]TJ
-9.5496 -1.1174 TD
[(descriptively)-329.1(form)-328.1(a)-324.8(dumbbell-like)-329.4(structure.)-326.7(The)-328.2(i)-18.5(m)-25.4(m)-19.6(u)-18.4(n)-18.4(o)-24.1(-)]TJ
0 -1.1116 TD
.0189 Tc
[(mo)-5.2(dul)-5.4(ato)-5.2(r).6(y)-431.5(non)-5.2(meth)-5.2(yla)-6.4(t).4(ed)]TJ
11.9168 0 TD
.0207 Tc
[(CG)-430.5(motifs)-429.5(are)-425.1(p)2.3(lace)-4.6(d)-423.9(i)-3.6(n)-423.9(t)2.2(he)]TJ
-11.9168 -1.1116 TD
0 Tc
[(single-stranded)-284.9(loops,)-285.3(double-stranded)-285(stem,)-280.9(or)-278.6(in)-278.8(both.)]TJ
1.0137 -1.1174 TD
[(He)18.8(re)25.5(,)-343.2(w)0(e)-326.8(p)0(r)20.9(e)0(s)19.9(e)0(n)19.7(t)-341(th)26.5(e)-342.1(m)0(o)19.6(l)0(e)19.6(c)15(ul)20.7(ar)-331.6(de)19.7(si)20.9(gn)-324.7(pa)19.7(th)-330.6(to)-324.9(MG)19.1(N1)20(70)20.8(3)]TJ
-1.0137 -1.1116 TD
[(fr)20.9(om)-308.7(o)16.2(t)0(h)20.7(e)0(r)-308.6(m)0(o)19.6(l)0(e)25.3(c)0(u)19.7(l)0(e)19.6(s)-317.7(of)-307.4(th)26.5(e)-319(d)0(S)21(L)0(I)19.7(M)-318.8(f)16.2(a)0(m)18.5(i)0(l)20.6(y)0(.)-304(T)0(o)-308.7(a)0(s)19.9(s)0(a)19.9(y)-312.1(th)20.7(e)-319(r)0(e)19.7(-)]TJ
T*
[(sp)21(ec)18.5(ti)20.6(ve)-251(de)19.7(si)20.9(gn)-255.6(va)25.4(ri)20.7(an)19.7(ts)-255.6(fo)20.9(r)-266(a)15(ct)19.6(iv)20.7(at)19.5(io)20.7(n)-260.3(o)0(f)-255.6(t)0(h)20.7(e)-267.2(T)15(L)0(R)18.6(-)0(9)-255.6(p)0(a)19.7(t)0(h)20.7(w)15.3(ay)19.7(,)]TJ
0 -1.1174 TD
[(we)-355.6(r)21(st)-353.5(em)18.5(pl)20.7(oy)20.8(ed)-354.7(sp)21(ec)18.5(i)26.6(c)-370.9(c)0(e)24.3(l)0(l)-359.6(l)0(i)20.6(n)16.2(es)-360.3(of)-353.5(di)20.7(ff)20.9(er)19.7(e)15(n)0(t)-359.4(o)0(r)20.9(i)16(gi)20.7(n)-369.7(a)15(s)-369.5(a)]TJ
0 -1.1116 TD
[(mo)19.6(de)19.7(l)-168.3(s)0(y)21(s)0(t)20.9(e)0(m)-165.9(a)0(n)25.4(d)-173.9(la)19.6(te)19.5(r)-173.9(c)15(on)20.8(r)21(me)18.4(d)-173.9(o)0(u)26.6(r)-173.9(da)19.7(ta)-164.8(in)-157.8(hu)20.8(ma)18.4(n)-173.9(p)16.2(er)19.7(ip)20.7(he)19.7(ra)19.7(l)]TJ
T*
[(bl)20.7(oo)20.8(d)-352.4(m)0(o)19.6(n)0(o)20.8(n)0(u)20.8(c)0(l)25.3(e)0(a)18.5(r)-358.2(ce)18.5(l)16.1(l)0(s)-347.7(\()0(P)21(B)0(M)18.9(C)0(\))-343(f)0(r)20.9(o)0(m)-343.2(h)0(e)19.7(a)0(l)19.6(t)0(h)20.7(y)-352.4(do)20.8(no)20.8(rs)21.1(.)-354.8(T)0(h)19.6(e)]TJ
T*
[(ce)18.5(ll)-181(li)26.3(ne)-181.9(sy)21(st)20.9(em)18.5(s)-191(a)15(ll)20.6(ow)20(ed)-181.9(fo)20.9(r)-191.1(t)16.1(he)-181.9(de)19.7(te)19.6(ct)19.6(io)26.5(n)-191.2(o)0(f)-180.7(s)0(u)21(b)0(t)20.7(l)0(e)-176.3(d)0(i)20.7(f)0(f)20.9(e)0(r)19.7(e)0(n)19.7(c)0(e)18.5(s)]TJ
0 -1.1174 TD
[(in)-180.9(T)15(L)0(R)18.6(-)0(9)-180.7(a)15(ct)19.5(iv)20.7(at)19.6(io)20.7(n)-185.4(t)0(h)20.7(a)0(t)-176.3(w)0(o)20(u)0(l)20.7(d)-191.2(ha)25.4(ve)-181.9(be)19.7(en)-176.1(lo)20.7(st)-174.9(in)-180.9(PB)20(MC)-176.9(as)19.9(sa)19.9(ys)]TJ
0 -1.1116 TD
[(du)20.8(e)-209.6(t)0(o)-198.2(t)0(h)20.7(e)-209.6(in)20.7(di)20.7(vi)20.7(du)26.6(al)-199.3(va)19.7(ri)20.7(ab)19.7(il)20.6(it)20.6(y)-208.4(o)0(f)-198(P)0(B)20(M)0(C)-200(f)0(r)20.9(o)0(m)-199.3(d)16.2(on)20.8(or)20.9(s.)-200.2(On)-198.9(th)20.7(e)]TJ
T*
[(ot)20.7(he)19.7(r,)-436.5(on)20.8(ly)-440.1(in)-440.1(PB)20(M)15.3(C)-451.4(mo)19.6(st)-439.9(as)19.9(pe)19.7(c)15(t)0(s)-439.9(o)0(f)-439.9(i)0(n)20.7(n)0(a)19.7(t)0(e)-441.2(a)0(n)19.7(d)-444.6(ad)19.7(ap)19.7(ti)20.6(ve)]TJ
0 -1.1174 TD
[(im)19.5(mu)25.4(ne)-377.7(ac)18.5(ti)20.6(va)25.4(ti)20.6(on)-376.6(by)-376.6(d)16.2(S)0(L)19.8(I)0(M)-377.4(m)0(o)25.4(l)0(e)19.6(c)0(u)19.7(l)0(e)19.6(s)-386.8(co)25.4(ul)20.7(d)-387(b)0(e)-377.7(a)15(ss)21.2(es)19.9(se)19.9(d.)]TJ
0 -1.1116 TD
[(Fi)20.9(na)19.7(ll)20.6(y,)-258(to)20.7(x)16.2(i)0(c)19.6(o)0(l)20.7(o)0(g)20.8(i)0(c)19.5(a)0(l)-256.9(s)0(t)20.9(u)0(d)20.8(i)0(e)19.6(s)-265.8(in)-261.5(ro)20.9(de)19.7(nt)26.5(s)-271.6(a)0(r)19.7(e)-267.2(re)19.7(po)20.8(rt)20.7(ed)19.7(.)]TJ
/F7 1 Tf
8.9663 0 0 8.9663 62.022 100.4598 Tm
[(Materials)-332.7(and)-338.2(Methods)]TJ
/F10 1 Tf
0 -1.8336 TD
[(TLR-9)-335.6(agonists)-333.4(for)-332.5(immunomodulation)]TJ
/F4 1 Tf
9.843 0 0 9.843 72 67.5779 Tm
[(MGN1703)-235(and)-229.1(other)-231.4(molecules)-239.3(of)-232.6(the)-229.2(dSLIM)-232(family)-233.9(were)]TJ
-1.0137 -1.1116 TD
[(generated)-273.9(as)-273.9(described)-272.5([43,44].)-272.6(The)-276.4(endotoxin)-270.5(content)-275.2(of)-267.1(all)]TJ
25.504 67.9184 TD
[(nucle)-8(otide)-208.5(molecules)-222.1(was)-212.5(determined)-217.6(by)-209.6(an)-216.5(endpoint)-211.8(limulus)]TJ
0 -1.1174 TD
[(ameb)-8(ocyte)-376.6(lysate)-377.6(test)-380(to)-376.7(be)-377.7(below)-382(10)-376.6(EU/mg)-377.6(DNA.)-378(If)-376.5(not)]TJ
0 -1.1116 TD
[(denoted)-200.2(otherwise,)-206.7(a)-198.1(nal)-195.6(concentration)-203.6(of)-198(1)]TJ
/F6 1 Tf
17.7111 0 TD
(m)Tj
/F4 1 Tf
.5529 0 TD
[(M)-197.8(was)-201(used)-195.4(for)]TJ
-18.264 -1.1116 TD
[(each)-284.4(molecule.)]TJ
1.0137 -1.1116 TD
[(To)-619.7(evaluate)-618.5(the)-620.9(effect)-620.7(of)-618.5(backbone)-617.1(modications)-621.6(or)]TJ
-1.0137 -1.1174 TD
-.0276 Tc
[(substitution)-184.2(o)5.9(f)-184.2(C)-.9(G)-185.1(m)-1.1(otif)5.9(s,)-186.5(we)-185.4(d)5.9(e)-1.1(signed)-184.2(s).3(everal)-184.3(variati)5.7(ons)-184(\()-86.3(M)5(od-1)]TJ
0 -1.1116 TD
0 Tc
[(to)-440.1(Mod-9\))-439.4(of)-439.9(the)-442.3(standard)-443(MGN1703,)-440(a)-440(dumbbell-shaped)]TJ
T*
[(molecule)-382.4(with)-374.2(two)-378.7(single-stranded)-377.1(loops)-379.8(of)-370.8(30)-376.6(nucleotides)]TJ
0 -1.1174 TD
[(each)-261.3(containing)-261.4(three)-255.6(nonmethylated)-261.3(CG)-257.5(motifs)-261.3(and)-257.9(a)-255.7(28-bp)]TJ
0 -1.1116 TD
[(double-stran)-9.8(ded)-183(stem.)-188.7(CG)-188.4(motifs)-186.4(were)-191.9(replaced)-186.4(by)-186.5(TG)-188.6(motifs)]TJ
T*
[(to)-307.6(investigate)-303.9(CG)-303.6(dependence)-304.8(in)-301.8(control)-302.8(molecules)-308.4(\(noCpG)]TJ
0 -1.1174 TD
[(ODN,)-285.8(noCG-MGN1703\).)]TJ
/F10 1 Tf
8.9663 0 0 8.9663 313.0582 580.1384 Tm
(Cells)Tj
/F4 1 Tf
9.843 0 0 9.843 323.0361 563.6975 Tm
[(RPMI-8226,)-222.4(Jurkat,)-218.5(MOLT-3,)-221.5(U937,)-221.8(NK-92,)-218(and)-217.6(YT)-223.1(cells)]TJ
-1.0137 -1.1116 TD
[(were)-358.9(obtained)-357(from)-351.1(the)-355.9(Deutsche)-352.9(Sammlung)-358(von)-348.9(Mikroor-)]TJ
0 -1.1174 TD
[(ganismen)-628.6(und)-619.6(Zellkulturen)-627.8(GmbH)-623.7(\(Braunschwe)-11.5(ig,)-622.1(Ger-)]TJ
0 -1.1116 TD
[(many\))-612.6(and)-609.2(were)-612.3(cultured)-610.4(as)-607.9(recommended.)-615.9(Cells)-612.5(were)]TJ
T*
[(stimulated)-291.4(with)-287.8(1)]TJ
/F6 1 Tf
7.2112 0 TD
(m)Tj
/F4 1 Tf
.5529 0 TD
[(M)-284.2(o)0(f)-290.2(respective)-292.2(molecules)-285.4(of)-290.2(the)-286.8(dSLIM)]TJ
-7.7641 -1.1116 TD
[(family)-395.1(or)-393.8(CpG)-396.9(ODN)-391.8(for)-394.9(48)-388.1(hours)-396.9(unless)-393.4(noted)-392.7(otherwise.)]TJ
0 -1.1174 TD
[(Human)-475.3(peripheral)-475.5(mononuclear)-477.7(blood)-472.2(cells)-474.4(were)-474.1(isolated)]TJ
0 -1.1116 TD
[(from)-322.3(peripheral)-325.7(blood)-316.7(of)-319(normal)-320.1(volunteers)-324.4(via)-321.4(Ficoll)-319(tech-)]TJ
T*
[(nique)-283.3(as)-285.4(described)-284(previously)-282.9([45,46].)]TJ
/F10 1 Tf
8.9663 0 0 8.9663 313.0582 451.6156 Tm
[(Flow)-338.7(cytometry)]TJ
/F4 1 Tf
9.843 0 0 9.843 323.0361 435.1747 Tm
[(Ce)18.6(ll)20.6(s)-260.1(w)0(e)18.8(r)0(e)-245.2(s)0(t)20.9(i)0(m)19.5(u)0(l)20.7(a)0(t)19.5(e)0(d)-251(w)15.3(it)20.6(h)-260.3(M)0(G)19.1(N)0(1)20(7)0(0)20.8(3)-260.3(an)25.4(d)-260.3(o)0(t)20.7(h)0(e)19.7(r)-260.3(mo)19.6(le)25.3(cu)19.7(le)19.6(s)]TJ
-1.0137 -1.1116 TD
[(of)-353.5(th)20.7(e)-359.4(d)0(S)21(L)0(I)19.7(M)-359.1(fa)19.7(mi)19.5(ly)-347.9(an)19.7(d)-358.2()0(o)21(w)-364.8(c)15(y)0(t)20.7(o)0(m)19.6(e)0(t)19.5(r)0(y)-347.7(w)0(a)18.8(s)-358(pe)19.7(rf)20.9(or)20.9(me)18.5(d)-358.2(a)0(s)]TJ
T*
[(de)19.7(sc)19.9(ri)20.7(be)19.7(d)-438.8([)0(4)20.9(3)16.2(,4)18.5(7])20.9(.)-435.4(B)0(r)19.8(i)0(e)19.6()0(y)21(,)-435.4(48)-428.4(ho)20.8(ur)20.9(s)-432.9(a)0(f)19.7(t)0(e)19.5(r)-438.8(st)20.9(im)19.5(ul)26.5(at)19.5(io)20.7(n,)-425(ce)18.5(ll)20.6(s)]TJ
0 -1.1174 TD
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T*
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T*
[(30)-382.3(mi)19.5(nu)20.8(te)19.6(s.)-378.7(Th)19.6(e)-393.9(c)0(e)18.5(l)0(l)20.6(s)-392.6(we)18.8(re)-383.5(su)21(b)16.2(s)0(e)19.9(q)0(u)20.8(e)0(n)19.7(t)0(l)20.6(y)-392.8(wa)18.8(sh)21(e)15(d)-392.8(wi)19.8(th)-382.5(PB)20(S)]TJ
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T*
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T*
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0 -1.1174 TD
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0 -1.1116 TD
[(fr)20.9(om)-412.4(an)19.7(a)15(l)0(y)20.7(s)0(i)20.9(s)0(.)-407.5(T)0(h)19.6(e)-422.7(m)15(e)0(a)18.5(s)0(u)21(r)0(e)19.7(m)0(e)18.4(n)16.2(ts)-411.1(we)18.8(re)-406.5(ca)18.5(rr)20.9(ie)19.6(d)-415.8(o)0(u)20.8(t)-421.7(us)21(in)20.7(g)-415.8(a)]TJ
T*
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[(Cytokine)-328.1(enzyme-linked)-325.7(immuno)-320.2(assays)-330.9(were)-324.4(performed)]TJ
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[(with)-276.2(supernatants)-281.5(of)-272.9(10)]TJ
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(6)Tj
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[(cells/mL)-278.7(that)-270.8(had)-275.2(been)-277.4(cultured)-270.5(for)]TJ
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[(48)-249.9(hours)-247.2(according)-243.9(to)-250(the)-246.5(manufacturers)-251.5(instruction)-244([IFN-)]TJ
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[(interleukin)-285.6(\(IL\)-12p40,)-286.2(IL-6,)-279.7(and)-280.9(IFN-)]TJ
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(a)Tj
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[(,)-279.9(R&D)-282.9(Systems].)]TJ
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[(Stability)-339.4(assay)]TJ
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T*
[(t)-15.9(o)10.6(gra)-15.9(p)9.5(h).3(y)-339.5(\().3(HPL)-15.9(C)8.5(\),)-336.1(an)-15.9(d)-323.4(g).3(e)-15.9(l)-324.7(el)-15.9(e)9.4(c)-.9(tro)-15.9(p)10.7(hor)-15.9(e)9.6(s).5(is)-15.9(.)-325.5(T)-.9(his)-339.3(s).5(t)-15.9(a)9.4(bili)-15.9(t)10.4(y)-339.5(data)]TJ
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8.9663 0 0 8.9663 62.022 749.6502 Tm
0 Tc
(2)Tj
46.5556 0 TD
[(SCHMIDT)-333.3(ET)-338.7(AL.)]TJ
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[(Toxicology)-338.3(studies)-335.3(in)-330.2(mice)]TJ
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(m)Tj
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(L)Tj
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[(que)12.8(ntl)13.7(y,)-194.6(liv)13.7(er)-193.4(an)13.9(d)-196.9(spl)14(een)-189.9(wer)12(e)-198.1(sto)14(red)-188.7(in)-192.4(4%)-193.3(par)12.8(afo)12.8(rm)13.9(ald)12.7(ehy)12.8(de)]TJ
T*
[(at)-567.9(roo)14(m)-572.5(tem)11.5(per)12.8(atu)12.7(re)14(.)-573.6(Par)13(afo)12.8(rma)11.6(lde)18.4(hyd)14(e-)13(xed)-563.2(sec)11.8(tio)13.7(ns)-566.5(of)]TJ
T*
[(spl)14(een)-270.6(and)-269.4(liv)13.7(er)-274(wer)12(e)-273(sta)12.9(ine)12.7(d)-277.6(wit)12.8(h)-277.6(hem)11.6(at)13.8(oxi)13.8(lin)13.7(/eo)12.7(sin)-268.2(for)-268.2(his)14(-)]TJ
0 -1.1174 TD
[(tol)13.7(ogi)13.8(cal)-380.1(rep)12.8(ort)13.9(.)-383.6(Ana)11.9(lys)14(is)-382.3(was)-373.8(per)12.8(for)14(med)-380.1(as)-383.3(a)-382.4(dou)14(ble)12.7(-bl)13.9(ind)]TJ
0 -1.1116 TD
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T*
[(ana)11.7(lys)14(is)-376.5(of)-370.8(org)14(an)-377.7(wei)11.8(ght)13.8(s.)-373(Mic)11.8(e)-376.6(stu)14(die)12.7(s)-381(w)0(e)13(r)0(e)-377.7(per)12.8(for)14(med)-368.6(in)]TJ
0 -1.1174 TD
[(acc)10.5(red)12.8(ite)12.6(d)-456.1(a)0(n)13.9(ima)11.5(l)-456.2(fac)11.7(ili)13.6(tie)18.3(s)-455.9(a)0(t)-452.7(Dir)13(ecc)10.5(io)]TJ
15.7816 .0461 TD
()Tj
.4089 -.0461 TD
[(n)-456.1(Gen)11.9(era)11.7(l)-456.2(d)0(e)-446.9(Agr)13.1(i-)]TJ
-16.1905 -1.1116 TD
[(cul)12.7(tur)13.9(a,)-247.6(Co)14(mun)12.7(ida)12.7(d)-248.8(d)0(e)-245.3(M)0(a)13(dri)13.9(d)-248.8(\(EX)11.9(02)14(3-U)13.1(SC\))-240.3(fol)13.9(lo)15(win)13(g)-248.8(the)]TJ
T*
[(res)13(pec)11.7(tiv)13.7(e)-180.8(sta)12.9(nda)12.8(rd)-169.2(ope)12.8(rat)12.7(ing)-170.5(pro)14(ce)12.8(dur)14(es,)-173.6(dir)13.9(ec)12.8(tiv)13.7(es,)-173.6(and)-165.7(loc)12.7(al)]TJ
0 -1.1174 TD
[(law)11.8(s:)-347.7([Eu)12.8(rop)14(ean)-339.7(Dir)13(ect)11.5(ive)12.7(s)-352.2(200)14(3/)15(65/)13.8(EC/)11.6(86/)13.8(609)14(/CE)11.6(E;)-343.3(Spa)13(n-)]TJ
0 -1.1116 TD
[(ish)-320(La)12.7(w)-330.3(R)0(D)-320.9(223)14(/19)13.8(88)15.1(;)-329.5(Hum)17.6(ane)-316.7(End)12.8(poi)13.8(nts)-314.3(Gui)13(dan)12.8(ce)-321.3(Doc)11.9(u-)]TJ
T*
[(men)11.6(t)-467.8(o)0(f)-457.2(the)-459.6(Or)14.2(gan)12.8(isa)12.9(tio)13.7(n)-467.6(for)-452.5(Eco)11.6(nom)12.7(ic)-458.5(Co-)13(ope)12.8(rat)12.7(ion)-452.7(and)]TJ
0 -1.1174 TD
[(Dev)11.9(elo)12.7(pme)11.6(nt)-526.5(ENV)11(/JM)13.1(/MO)12.1(NO)13.3(\(20)14(00\))14(7;)-532.2(and)-522.8(Fed)13(era)11.7(tio)13.7(n)-531(o)0(f)]TJ
0 -1.1116 TD
[(Lab)11.6(ora)12.8(tor)13.9(y)-277.6(A)0(n)14.2(ima)11.5(l)-277.7(Sci)12.8(en)13.9(ce)-275.2(Ass)13.5(oci)12.7(ati)12.6(ons)-262.3(gui)13.8(del)12.7(ine)12.7(s].)]TJ
/F7 1 Tf
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(Results)Tj
/F10 1 Tf
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[(MGN1703,)-338.5(a)-333.2(member)-334.8(of)-330.4(the)-334.8(dSLIM)-334.4(family)]TJ
/F4 1 Tf
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[(clinically)-464.4(relevant)-456(side)-454.8(effects,)-463.8(such)-454.6(as)-458.2(unspecic)-456.7(protein)]TJ
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T*
0 Tc
[(\(dSLIM\))-493.4(with)-489.3(natural)-494.1(phosphorodiester)-497.8(\(PO\))-494.6(DNA)-489.7(back-)]TJ
T*
[(bones)-363.6(lacking)-367.4(open)-362.7(3)]TJ
/F5 1 Tf
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()Tj
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[(and)-367.3(5)]TJ
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()Tj
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[(ends.)-365.9(Such)-362.5(covalently)-366.2(closed)]TJ
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[(constructs)-226.3(can)-218.7(be)-222.2(drawn)-226.4(as)-222(a)-221.1(dumbbell-like)-225.7(shape,)-218.4(where)-227.5(two)]TJ
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T*
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[(\(n)20.9(t\))-250(wi)19.8(th)-244.2(id)20.7(en)13.9(ti)20.6(ca)18.5(l)-254.7(s)0(e)14.1(q)0(u)20.8(e)0(n)19.7(c)0(e)18.5(s)0(,)-246.2(c)0(o)19.7(n)0(t)20.7(a)0(i)19.6(n)0(i)14.9(n)0(g)-244.1(t)0(h)20.7(r)0(e)19.7(e)-261.4(no)20.8(nm)19.6(et)19.5(hy)20.8(la)19.5(te)19.5(d)]TJ
T*
[(CG)-459.1(motifs)-457.1(each)-462.9(\(Fig.)-457(1A\).)-462.6(The)-460.7(MGN1703)-459.6(sequence)-462.5(was)]TJ
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[(conrmed)-334.7(by)-330.5(standard)-333.6(sequencing)-331.2(of)-330.5(the)-332.9(primary)-332.7(ODN)-334.2(be-)]TJ
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[(fore)-529.6(the)-528.7(ligation)-534.6(step.)-533.1(Integrity)-529.8(of)-532.1(the)-528.7(covalently)-533.3(closed)]TJ
T*
[(structure)-329(was)-333.4(assayed)-333.4(via)-327.1(exonuclease)-334.7(digestion)-333.8(and)-327(subse-)]TJ
T*
[(quent)-277.5(gel)-275.3(electrophoresis)-286.1(or)-272.9(HPLC.)-281.5(MGN1703,)-278.8(when)-277.1(stored)]TJ
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[(at)-274.2(a)-278.7(temperature)-277.4(of)]TJ
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(-)Tj
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()Tj
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[(C,)-276.3(was)-275.8(stable)-279.7(for)-273.9(a)-278.7(minimum)-276.6(of)-278.6(36)]TJ
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[(MGN1703)-335(increases)-331.5(expression)-335.9(of)-330.4(immunological)]TJ
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[(CpG)-379.6(ODN)-380.3(are)-380(known)-380.8(to)-376.7(stimulate)-382.4(expression)-381.7(of)-376.5(immu-)]TJ
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[(nological)-317.9(markers)-316.3(on)-313.2(the)-315.6(cell)-318(surface)-322(and)-315.5(production)-317.7(of)-313.2(cy-)]TJ
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[(on)-301.7(various)-308.3(cell)-312.3(lines)-306.2(representing)-310.5(components)-308.3(of)-307.4(innate)-308.7(and)]TJ
T*
[(adaptive)-519.4(immune)-517.2(responses,)-516.2(like)-518.4(B-lineage)-521.5(cells)-514.8(\(RPMI-)]TJ
T*
[(8226\),)-187.5(T-lineage)-193.4(cells)-186.4(\()-127.8(Jurkat,)-189.7(MOLT-3\),)-188.1(monocytes)-192(\(U937\),)]TJ
0 -1.1174 TD
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ET
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124.554 410.4 m
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W n
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360.926 0 0 267.137 124.554 143.263 cm
/Im1 Do
Q
Q
BT
/F8 1 Tf
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[(FIG.)-365.5(1.)]TJ
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(\(A\))Tj
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(black)Tj
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[(.)-412.2(ds,)-414(double)-410.4(strand;)-411.4(ss,)-413.9(single)-410.4(strand)]TJ
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(\(B\))Tj
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T*
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(\(C\))Tj
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(\(D\))Tj
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(g)Tj
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[(\))-277.4(ELISA)-278.6(of)-284.2(supernatant)-279.5(from)-281.5(natural)-280.3(killer)-278.3(\(NK\)-92)-279.2(cells.)]TJ
/F8 1 Tf
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[(\(E,)-282.8(F\))]TJ
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[(Example)-282.4(of)-278.4(a)-278.6(concentration-)]TJ
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T*
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[(\(G,)-392.3(H\))]TJ
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3.2651 0 TD
[(Concentration-dependent)-400(activation)-399.9(of)-393.6(IFN-)]TJ
/F6 1 Tf
18.0646 0 TD
(a)Tj
/F4 1 Tf
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[(and)-390(IL-6)-396.7(cytokine)-396.4(production)-391.5(from)-396.7(healthy)-395.4(donor)]TJ
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[(MGN1703,)-338.5(A)-331.6(POTENT)-335.4(AND)-337.2(SAFE)-333.1(TLR-9)-336.8(AGONIST)-30299.2(3)]TJ
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